Pharmaceutical solutions of levosimendan

ABSTRACT

Levosimendan solutions for pharmaceutical use, and particularly for intravenous administration. The solutions of the invention have enhanced stability and they are particularly useful as infusion or injection solutions or infusion concentrates. Levosimendan is useful in the treatment of congestive heart failure.

TECHNICAL FIELD

[0001] The present invention relates to levosimendan solutions forpharmaceutical use, and particularly for intravenous administration. Thesolutions of the invention have enhanced stability and they areparticularly useful as infusion or injection solutions or infusionconcentrates. Levosimendan, or(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,is useful in the treatment of congestive heart failure.

BACKGROUND OF THE INVENTION

[0002] Levosimendan, which is the (−)-enantiomer of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and methods for its preparation aredescribed in EP 565546 B1 and WO 97/35841. Levosimendan is potent in thetreatment of heart failure and has significant calcium dependent bindingto troponin. Levosimendan is represented by the formula:

[0003] The hemodynamic effects of levosimendan in man are described inSundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066.Pharmacokinetics of levosimendan in man after i.v. and oral dosing isdescribed in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol.,26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment ofmyocardial ischemia is described in WO 93/21921. Transdermalcompositions of levosimendan are described in WO 98/01111. Clinicalstudies have confirmed the beneficial effects of levosimendan in heartfailure patients.

[0004] Administration of a drug by parenteral, e.g. intravenous,administration provides a number of advantages including the following:

[0005] an almost immediate response may be obtained by administering byintravenous injection or infusion a solution, usually aqueous, of thedrug;

[0006] the therapeutic response may be more readily controlled byadministering the drug parenterally; and

[0007] a drug can be administered parenterally to a patient when itcannot be administered orally because of the unconscious state of thepatient, or because of inactivation or lack of absorption in theintestinal tract.

[0008] The manufacture of levosimendan solutions, and particularlysolutions suitable for intravenous use, involves a number of problemswhich are caused by the sensitivity of levosimendan against chemical andphysical influences. In solutions levosimendan is sensitive to chemicaldegradation which limits the shelf-life of solutions and may produceundesirable degradation products. Levosimendan is also poorly soluble inwater and precipitates easily from aqueous solutions. The precipitationof intravenous solutions is extremely dangerous because particulatematerial may occlude the blood vessels. The solubility of levosimendandecreases further strongly when the pH is lowered from neutral, so thatlow pH would in principle seem unfavourable. Thus, there is a need forimproved aqueous formulations of levosimendan which are chemically andphysically stable under prolonged storage and suitable for intravenousadministration.

SUMMARY OF THE INVENTION

[0009] It has now been found that the chemical stability of levosimendansolutions can be significantly improved if the pH of the solution islowered from neutral to lower than 5, preferably to 4.5 or lower, mostpreferably to 3-4.2. Furthermore, it has been found that theprecipitation of the active ingredient can be prevented in suchchemically stable solutions.

[0010] Thus, in one aspect, the present invention provides apharmaceutical aqueous solution with improved stability comprising

[0011] (a) levosimendan or a pharmaceutically acceptable salt thereof asan active ingredient, the pH-value of the solution being lower than 5,preferably about 4.5 or lower, most preferably from about 3 to about4.2, and optionally

[0012] (b) a solubility enhancing agent.

[0013] In another aspect, the invention provides an aqueous intravenousinfusion solution with improved stability comprising

[0014] (a) levosimendan or a pharmaceutically acceptable salt thereof asan active ingredient, the pH-value of the solution being lower than 5,preferably about 4.5 or lower, most preferably from about 3 to about4.2; and optionally

[0015] (b) a solubility enhancing agent.

[0016] Still in another aspect the invention provides an intravenousinfusion concentrate, particularly to be diluted with an aqueous vehiclebefore use, comprising

[0017] (a) levosimendan or a pharmaceutically acceptable salt thereof asan active ingredient;

[0018] (b) organic solvent comprising ethanol;

[0019] (c) a stability enhancing amount of a pharmaceutically acceptableorganic acid having pKa in the range of from 2 to 4; and optionally

[0020] (d) a solubility enhancing agent.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Levosimendan is crystalline powder at room temperature and haspKa of 6.26. At room temperature the solubility of levosimendan inphosphate buffer is 0.4 mg/ml (pH 7.4), 0.03 mg/ml (pH 6) and 0.02 mg/ml(pH 2). Thus, the water solubility of levosimendan decreases quitesharply when pH is lowered below neutral. However, it has been foundthat it is possible to prepare pharmaceutically acceptable aqueoussolutions of levosimendan with pH lower than 5. Such solutions arechemically and physically stable over an extended period of time and,therefore, they are particularly suitable for pharmaceutical use.

[0022] In one aspect, the invention provides a pharmaceuticalcomposition which comprises levosimendan or a pharmaceuticallyacceptable salt thereof as an active ingredient in an aqueous solutionwith pH lower than 5, preferably about 4.5 or lower, and most preferablyfrom about 3 to about 4.2. The composition of the invention isparticularly useful in various pharmaceutical applications in whichlevosimendan must be stored in the form of an aqueous solution for anextended period of time.

[0023] The therapeutically effective amount of levosimendan included inthe composition of the invention depends e.g. on the administrationroute of the composition, the treatment procedure and the condition tobe treated. In general, the amount of levosimendan in the composition iswithin the range of about 0.001-5 mg/ml. The daily dosage oflevosimendan in man is within the range of about 0.1-50 mg, preferablyabout 0.2-20 mg, depending on the administration route, age, body weightand condition of the patient. Preferred peak plasma levels oflevosimendan in steady state for the treatment of congestive heartfailure are within the range of from about 1 to about 300 ng/ml, morepreferably from about 10 to about 150 ng/ml, and especially from about20 to about 60 ng/ml. Levosimendan can be administered intravenouslywith the infusion rate in the range of about 0.005-100 μg/kg/min,typically 0.01 to 10 μg/kg/min, more typically about 0.02 to 1μg/kg/min. For the treatment of heart failure, with continuous infusionthe suitable rate is 0.05-0.4 μg/kg/min of levosimendan.

[0024] Salts of levosimendan may be prepared by known methods.Pharmaceutically acceptable salts are useful as active medicaments,however, preferred salts are the salts with alkali or alkaline earthmetals.

[0025] The control of pH of the composition is essential to maintain therequired stability of the active ingredient. Therefore, a suitablepharmaceutically acceptable acidic compound or buffer system in anamount effective to maintain the pH of the composition in the desiredrange, may be used. Preferred acidic compounds include pharmaceuticallyacceptable organic acids having pKa in the range of from about 2 toabout 4. Such acids include 2-hydroxy alkanoic acids, such as citricacid, lactic acid, tartaric acid or malic acid. If a pharmaceuticallyacceptable buffer system is used, it is selected from a group of buffersthat are effective to maintain pH below 5, preferably at 4.5 or lower,most preferably in the range of about 3-4.2, which buffers are wellknown in the art. Most preferably the buffer may be selected fromcitrate, acetate, phosphate and lactate buffers. The preparation ofbuffer systems is well known for one skilled in the art. In general, theacidic compound or buffer is used in an amount necessary to adjust thepH into the desired range. However, the amount used must bepharmaceutically acceptable.

[0026] The composition of the invention may also comprise a solubilityenhancing agent. The term “solubility enchancing agent” means herein asubstance capable of increasing the amount of levosimendan that can bemaintained in a dissolved state in an aqueous solution, including theprevention of crystallization or crystalline growth of levosimendan.Suitable solubility enhancing agents include co-solvents such as ethanolor propylene glycol, surfactants and polymeric substances such aspolysorbates, polyalkylene glycols (e.g. polyethylene glycol),poloxamers or polyvinylpyrrolidone, and oily fatty acids and their mono-or diglyceryl esters such as linoleic acid or glyceryl monolaurate. Ingeneral, the amount of the solubility enhancing agent is within therange of about 0.001-80%, preferably 0.005-10%, most preferably 0.01-5%,by weight of the composition. For intravenous administration, whereinthe choice of acceptable adjuvants is limited, polyvinylpyrrolidone orethanol or a mixture thereof is the preferred solubility enhancing agentpolyvinylpyrrolidone being the most preferred. Suitable polyvinylpyrrolidones are those with a number average weight below 40,000, moresuitably below 5000, and particularly about 2,500. Such a polyvinylpyrrolidone is exemplified by Kollidon PF12 (registered trademark).

[0027] It will be understood that various additives commonly used inthis field of the art, such as preservatives, can be also included inthe composition of the invention.

[0028] In another aspect, the invention provides an aqueous intravenoussolution comprising levosimendan or a salt thereof as an activeingredient the pH-value of the solution being lower than 5, preferablyabout 4.5 or lower, and most preferably from about 3 to about 4.2. Theaqueous intravenous solution, which can be in a form of e.g. aninjection or infusion solution, of the invention is chemically andphysically stable under storage conditions over an extended period oftime. Preferably the aqueous intravenous solution is a ready to useintravenous solution for infusion or bolus injection.

[0029] The amount of levosimendan included in the aqueous intravenoussolution of the invention depends e.g. on the treatment procedure andthe condition to be treated, but is generally a therapeuticallyeffective amount. The amount may vary e.g. within the range of about0.001-1.0 mg/ml, preferably about 0.005-0.5 mg/ml, most preferably about0.01-0.1 mg/ml.

[0030] For maintaining the pH of the aqueous intravenous composition ofthe invention in the desired range a suitable pharmaceuticallyacceptable acidic compound or buffer system may be used as describedabove.

[0031] The aqueous intravenous composition of the invention may alsocomprise a solubility enhancing agent for increasing the amount oflevosimendan that can be maintained in a dissolved state in an aqueoussolution, including the prevention of crystallization or crystallinegrowth of levosimendan. For intravenous administration, wherein thechoice of acceptable adjuvants is limited, polyvinylpyrrolidone orethanol or a mixture thereof is the preferred solubility enhancing agentpolyvinylpyrrolidone being the most preferred. The amount of thesolubility enhancing agent in the aqueous intravenous composition isgenerally within the range of about 0.001-20%, preferably 0.005-5%, byweight of the aqueous intravenous composition. The preferred amount ofpolyvinylpyrrolidone is within the range of about 0.005-0.5% by weightof the aqueous intravenous composition.

[0032] The aqueous intravenous composition of the invention may alsocomprise a physiologically and pharmaceutically acceptable compoundeffective to render the aqueous intravenous composition isotonic, i.e.to have an osmotic pressure corresponding to that of a 0.9% solution ofsodium chloride. Typical examples of such compounds are chloride saltssuch as NaCl and saccharides such as sorbitol, mannitol anddextrose/glucose. The preparation of isotonic solutions is well knownfor one skilled in the art.

[0033] The aqueous intravenous composition of the invention may beprepared e.g. by dissolving levosimendan and other adjuvants intosterile isotonic aqueous vehicles, e.g. 0.9% solution of sodium chloridewhile,stirring. Alternatively a suitable amount of isotonic renderingcompound is dissolved together with levosimendan and other adjuvantsinto aqueous vehicle, e.g. sterile distilled water. The solution may bealso prepared by dissolving levosimendan and other adjuvants first insuitable solvent such as ethanol, and diluting the solution with sterileisotonic aqueous vehicles. The bulk solution is filtered and filled intoinfusion bottles or ampules. The product is sterilized preferably usingautoclaving in a manner known in the art.

[0034] In yet another aspect the invention provides a pharmaceuticalsolution, particularly an intravenous infusion concentrate to be dilutedwith an aqueous vehicle before use, comprising (a) levosimendan or apharmaceutically acceptable salt thereof as an active ingredient, (b)pharmaceutically acceptable organic solvent comprising ethanol,preferably dehydrated ethanol, and (c) a stability enhancing amount of apharmaceutically acceptable organic acid having pKa in the range of fromabout 2 to about 4. It has been found that the pharmaceuticallyacceptable organic acid having pKa in the range of from about 2 to about4 improves the stability of levosimendan in the concentrate solutions ofthe invention. It has also been found that the concentrate solutions ofthe invention can be successfully diluted with an aqueous infusionvehicle to obtain aqueous intravenous solutions which are chemically andphysically stable over an extended period of time.

[0035] The amount of pharmaceutically acceptable organic solvent isgenerally within the range of 90-99.9%, preferably 95-99.9%, by weightof the concentrate solution of the invention. Typically at least about50% by weight of the solvent is ethanol. More suitably, the solventconsists essentially of ethanol, whereby at least 90%, preferably atleast 95%, more preferably at least 99%, by weight of the solvent isethanol. Most preferably the solvent consists solely of ethanol,preferably dehydrated ethanol.

[0036] The amount of said pharmaceutically acceptable organic acid ispreferably within the range of 0.005-2%, preferably 0.01-1%, by weightof the concentrate solution. Said pharmaceutically acceptable organicacid is a preferably a 2-hydroxy alkanoic acid. Such acids, includecitric acid, lactic acid, tartaric acid and malic acid the mostpreferred being citric acid.

[0037] The amount of levosimendan included in the concentrate solutionof the invention is generally an amount which is therapeuticallyeffective. The amount may vary e.g. within the range of about 0.1-10mg/ml, preferably about 0.5-8 mg/ml, most preferably about 1-5 mg/ml.

[0038] The concentrate solution of the invention may also comprise asolubility enhancing agent for increasing the amount of levosimendanthat can be maintained in a dissolved state in an aqueous solution,including the prevention of crystallization or crystalline growth oflevosimendan. The amount of the solubility enhancing agent in theconcentrate solution of the invention is generally within the range ofabout 0.01-5%, by weight of the composition. The solubility enhancingagent can be selected as described above. The most preferred solubilityenhancing agent is polyvinylpyrrolidone. The preferred amount ofpolyvinylpyrrolidone is generally within the range of about 0.5-2%, byweight of the concentrate composition.

[0039] A particularly preferred concentrate solution for intravenousinfusion comprises

[0040] (a) levosimendan or a pharmaceutically acceptable salt thereof inamount of 0.01-1.0% by weight,

[0041] (b) dehydrated ethanol in amount of 95-99.5% by weight,

[0042] (c) citric acid in amount of 0.03-0.6% by weight, and

[0043] (d) polyvinylpyrrolidone in amount of 0.5-2% by weight.

[0044] The concentrate solution may be prepared by dissolving stabilityenhancing organic acid, levosimendan and the optional solubilityenhancing agent and possible other additives to the solvent in thesterilized preparation vessel under stirring. The resulting bulksolution is filtered through a sterile filter. The sterilization methodof the product is preferably a sterile filtration, because ethanolsolution cannot be autoclaved due to the explosion risk. The sterilefiltered bulk solution is aseptically filled into injection vials andclosed with rubber closures.

[0045] The concentrate solution for intravenous infusion is diluted withan aqueous vehicle before use. Typically the concentrate solution isdiluted with aqueous isotonic vehicles for intravenous infusion, such as5% glucose solution or 0.9% NaCl solution. The concentrate infusion isdiluted such that an aqueous intravenous solution is obtained, whereinthe amount of levosimendan is generally within the range of about0.001-1.0 mg/ml, preferably about 0.005-0.5 mg/ml, most preferably about0.01-0.1 mg/ml, depending e.g. on the treatment procedure and thecondition to be treated.

[0046] The invention is illustrated but in no way limited, by thefollowing examples.

EXAMPLE 1

[0047] Concentrate Solution for Intravenous Infusion (a) levosimendan2.5 mg/ml (b) Kollidon PF12 10 mg/ml (c) citric acid 2 mg/ml (d)dehydrated ethanol ad 1 ml (785 mg)

[0048] The concentrate solution was prepared by dissolving citric acid,Kollidon PF121 and levosimendan to dehydrated ethanol in the sterilizedpreparation vessel under stirring. The resulting bulk solution wasfiltered through a sterile filter (0.22 μm). The sterilization method ofthe product was sterile filtration, because ethanol solution cannot beautoclaved due to the explosion risk. The sterile filtered bulk solutionwas then aseptically filled into 8 ml and 10 ml injection vials (with 5ml and 10 ml filling volumes) and closed with rubber closures. Theproduct has a shelf-life of 2 years in 2-8° C.

EXAMPLE 2

[0049] The effect of citric acid on the chemical stability oflevosimendan in ethanolic infusion concentrate solutions stored indifferent temperatures was studied. The solutions were prepared asdescribed in Example 1. The results are shown in Tables 1 and 2. In theTables “OR-1746” refers to(4-Ethoxy-6-imino-5-{[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]hydrazono}-5,6-dihydro-1(H)-pyrimidin-2-ylidene)-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenylazo]acetonitrile.TABLE 1 Effect of citric acid on the chemical stability of levosimendan.All solutions contain levosimendan (1.25 mg/ml), Kollidon PF12 (10mg/ml) and dehydrated ethanol (ad 1 ml). Citric acid Storage time/Amountof degradation product (OR-1746) mg/ml 2-8° C. 40° C. 0  5 weeks/0.34% 5 weeks/10.9% 0.25 13 weeks/0.29% 13 weeks/6.2% 0.50 13 weeks/0.20% 13weeks/4.4% 0.75 13 weeks/0.16% 13 weeks/3.5% 1.00 13 weeks/0.13% 13weeks/3.0% 1.50 13 weeks/0.10% 13 weeks/2.2% 2.00 13 weeks/0.10% 13weeks/1.7%

[0050] TABLE 2 Effect of citric acid on the chemical stability oflevosimendan. All solutions contain levosimendan (2.50 mg/ml), KollidonPF12 (10 mg/ml) and dehydrated ethanol (ad 1 ml). Citric acid Storagetime/Amount of degradation product (OR-1746) mg/ml 2-8° C. 40° C. 0 12months/3.94% nd 2.0  4 months/0.20% 4 months/5.6% 12 months/0.39% nd 18months/0.59% nd 2.5  4 months/0.16% 4 months/3.2% 12 months/0.28% nd 18months/0.47% nd

[0051] The results show that citric acid significantly improves thechemical stability of levosimendan in infusion concentrate solutions.

EXAMPLE 3

[0052] Aqueous Solution for Infusion, pH 3.9 (a) levosimendan 0.025mg/ml (b) Kollidon PF12 0.10 mg/ml (c) citric acid 0.02 mg/ml (d)ethanol 7.85 mg/ml (e) sodium chloride 9.0 mg/ml (e) water ad 1 ml

[0053] The above aqueous infusion solution was obtained by diluting theinfusion concentrate solution of Example 1 with isotonic (0.9%) sodiumchloride solution such that the resulting aqueous solution contained0.025 mg/ml of levosimendan. The diluted solution was clear with noprecipitation.

[0054] The chemical stability of levosimendan in the aqueous solution ofExample 3 was studied after 24 hour storage (at room temperature) andafter one month storage (at 2-8° C.). The results are shown in Table 3.“OR-1420” refers to(E)-2-cyano-2-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]acetamide.TABLE 3 The chemical stability of levosimendan in a solution of Example3 after the storage of 24 hours (at room temperature 25° C.) and afterthe storage of one month (at 2-8° C). 0 h 24 h 1 month Degradationproduct OR-1420 < < 0.1% Degradation product OR-1746 0.1% 0.1% < Unknowndegradation products < < < pH 3.9 nd 3.9

[0055] For comparison, the chemical stability of levosimendan inReference solutions having pH of 7-8 was studied after the storage of 2and 5 days at 8-15° C. and room temperature. The results are shown inTable 4.

[0056] Reference Solutions: (a) levosimendan 0.01-0.25 mg/ml (b) sodiumchloride 9 mg/ml (c) sodium carbonate monohydr. 0.02-0.5 mg/ml (d)hydrochloric acid 0.1 M to adjust pH to 7-8 (e) water ad 1 ml

[0057] Table 4. The chemical stability of levosimendan in Referencesolutions (0.01, 0.1 and 0.25 mg/ml of levosimendan) having pH of 7-8after the storage of 2 and 5 days at 8-15° C. and room temperature (25°C.). Levosi- mendan 2 days 5 days mg/ml 0 h 8-15° C./25° C. 8-15° C./25°C. Degradation 0.01 < 1.6%/3.3% 2.2%/6.0% product 0.1 1.5% 1.1%/1.8%1.8%/5.3% OR-1420 0.25 0.4% 0.8%/2.2% 1.4%/4.2% Unknown 0.01 nd nd nddegradation 0.1 < 0.2%/0.4% 0.2%/0.6% products 0.25 < 0.3%/0.5%0.3%/0.9% pH 0.01 7.2 7.2/7.3 7.3/7.3 0.1 7.8 7.8/7.8 8.0/8.0 0.25 7.87.8/7.8 8.0/8.0

[0058] The results show that degradation of levosimendan issignificantly retarded in the solution of Example 3 compared toReference solutions. In the Reference solutions significant amounts ofdegradation products are formed already after the storage of 5 days,whereas the solution of Example 3 is stable even after the storage ofone month. It can be also noted that the pH tends to increase inReference solutions.

1. A pharmaceutical aqueous solution comprising levosimendan or a saltthereof as an active ingredient the pH-value of the solution being lowerthan 5, preferably about 4.5 or lower, and optionally a solubilityenhancing agent.
 2. A solution according to claim 1 the pH-value of thesolution being in the range of from about 3 to about 4.2.
 3. Aqueousintravenous infusion solution comprising levosimendan or a salt thereofas an active ingredient the pH-value of the solution being lower than 5,preferably about 4.5 or lower, and optionally a solubility enhancingagent.
 4. A solution according to claim 3 the pH-value of the solutionbeing in the range of from about 3 to about 4.2.
 5. A solution accordingto claim 3 or 4, wherein the solubility enhancing agent ispolyvinylpyrrolidone or ethanol.
 6. A pharmaceutical solution,particularly an intravenous infusion concentrate, comprising (a)levosimendan or a pharmaceutically acceptable salt thereof as an activeingredient, (b) pharmaceutically acceptable organic solvent comprisingethanol, (c) a stability enhancing amount of a pharmaceuticallyacceptable organic acid having pKa in the range of from 2 to 4, andoptionally (d) a water-solubility enhancing agent.
 7. A solutionaccording to claim 6, wherein the amount of said solvent is 90-99.9%,preferably 95-99.9%, by weight of the solution.
 8. A solution accordingto claim 6 or 7, wherein the amount of said organic acid is 0.005-2%,preferably 0.01-1%, by weight of the solution.
 9. A solution accordingto any of claims 6-8, wherein pharmaceutically acceptable organic acidis a 2-hydroxy alkanoic acid.
 10. A solution according to claim 9,wherein pharmaceutically acceptable organic acid is citric acid, lacticacid, tartaric acid or malic acid.
 11. A solution according to claim 6,wherein the amount of the water-solubility enhancing agent is 0.1-5% byweight.
 12. A solution according to claim 6, wherein thewater-solubility enhancing agent is polyvinylpyrrolidone.
 13. A solutionaccording to claim 6 comprising (a) levosimendan or a pharmaceuticallyacceptable salt thereof in amount of 0.01-1.0% by weight, (b) dehydratedethanol in amount of 95-99.5% by weight, (c) citric acid in amount of0.03-0.6% by weight, and (d) polyvinylpyrrolidone in amount of 0.5-2% byweight.